Ouinoxalinyl-oxazolidines and -oxazines

ABSTRACT

NOVEL 2-QUINOXALINYL-OXAZOLIDINE-3-AMIDES AND -SULFONAMIDES AND 2-QUINOXALINYL-OXAZINE-3-AMIDES AND -SULFONAMIDES (I) ARE PROVIDED, WITH PHARMACOLOGICAL ACTIVITY AS NERVOUS SYSTEM DEPRESSANTS AND UTILITY TO INDUCE CALMING. COMPOUNDS (I) ARE PREPARED BY CONDENSING A ((2-QUINOXALINYLMETHYLENE)AMINE)ALKANOL (II) WITH A BENZYOL- OR PHENYLSULFONYL-CHLORIDE (III).

United States Patent 3,647,790 QUINOXALINYL-OXAZOLIDINES AND -OXAZINESJohn R. Potoski, Rosemont, and Meier E. Freed, Philadelphia, Pa.,assignors to American Home Products Corporation, New York, N.Y. 1 NoDrawing. Filed Apr. 8, 1969, Ser. No. 814,442 Int. Cl. C07d 87/06 US.Cl. 260244 R 11 Claims ABSTRACT OF THE DISCLOSURE Novel2-quinoxalinyl-oxazolidine-3-amicles and -sulfonamides and2-quinoxalinyl-oxazine-3-amides and -sulfonamides (I) are provided, withpharmacological activity as nervous system depressants and utility toinduce calming. Compounds (1) are prepared by condensing a[(Z-quinoxalinylmethylene)amine]alkanol (II) with a benzoylorphenylsulfonyl-chloride (III).

- This invention relates to quinoxalinyl-oxazolidines and -oxazines, andmore particularly to Z-quinoxalinyl-oxazolidine-3-amides and-sulfonamides and to 2-quinoxalinyl-oxazine-3-amides and -sulfonamideshaving pharmacological activity.

DESCRIPTION OF THE INVENTION The compounds contemplated by thisinvention are those of Formula I:

wherein Y is'CO or SO 1 I nis0or1,mis1,2or3; R is (lower)alkyl,(lower)alkoxy, halo, nitro or trifluoromethyl; v

when m is 1 or 3', 4', 5'-trirnethoxy when m is 3, R is hydrogen orphenyl, R is hydrogen when n is 1, R is hydrogen or methyl and R and Rare hydrogen.

3,647,790 Patented Mar. 7, 1972 Especially preferred embodiments are thecompounds of Formula I which are:

2- Z-quinoxalinyl) -3- (p-tolylsulfonyl) oxazolidine;

3 p-fiuorophenylsulfonyl -2- (2-quinoxaliny1) oxazolidine;

2- (Z-quinoxalinyl) -3 3,4,5 -trimethoxybenzoyl) oxazol idinetetrahydro-2- (2- quinoxalinyl) -3- (p-tolylsulfonyl) -2H- 1,3 -oxazine;

S-phenyl-Z- (2- quinoxalinyl) -3- p-tolysulfonyl) oxazolidine;

4-methtyl-5-phenyl-2- (2- quinoxalinyl) -3- (p-tolylsulfonyl)oxazolidine;

3 (pfluorophenylsulfonyl) -2- (Z-quinoxalinyl) oxazolidine;

2- (Z-quinoxalinyl) -3- 3,4,5-trirnethoxybenzoyl) oxazolidine;

tetrahydro-2- Z-quinoxalinyl) -3- (p-tolysulfonyl) -2H- 1,3-oXazine;

S-phenyl-Z- (2-quinoxalinyl) -3 (p-tolylsulfonyl) oxazolidine;

4-methyl-5-phenyl-2- (Z-quinoxalinyl) -3- (p-tolylsulfonyl oxazolidine;

2- 6-nitro-2-quinoxalinyl) -3 (p-tolylsulfonyl) oxazolidine;

3- (2,5 -dichlorophenylsulfonyl) -2- (Z-quinoxalinyl) oxazolidine;

3 p-chlorophenylsulfonyl) -tetrahydro-2- (quinoxalinyl) 2H-l,3-oxazine;

3 p-fluorophenylsulfonyl) -tetrahydro-2- (Z-quinoxalinyl) -2H- 1,3-oxazine 2- (6,7-dichloro-2- quinoxalinyl) -3- (p-tolylsulfonyl)oxazolidine;

3- (p-fluorophenylsulfonyl) -tetrahydro-2- (6,7-dichloro- 2-quinoxalinyl) -2H- 1,3 -oxazine; and

3- p-fluorophenylsulfonyl) -tetrahydro-2- (6,7-dimethoXy-2-quinoxalinyl) -2H- 1, 3-oxazine.

Compounds of Formula I are pharmacologically active as central nervoussystem depressants and are of value to induce calming.

When used herein and in the appended claims, the term (lower)alkylcontemplates hydrocarbon groups, straight chain and branched, of fromabout 1 to about 6 carbon atoms, illustrative members of which aremethyl, ethyl, n-propyl, i-propyl, n-butyl, t-buyl, n-pentyl, n-hexyl,Z-methylpentyl and the like. With respect to substituents R R and Rpreferred (lower)alkyl groups have a maximum of about 3 carbon atoms.Also contemplated are analogs and derivatives of (lower) alkyl groups,such as (lower)alkoxy which are alkyl-O-groups wherein the alkyl groupis as defined as hereinabove, illustrative members of which are methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentoxy, n-hexoxy,Z-methylpentoxy, and the like. Hydroxy(lower) alkyl contemplates (lower)alkyl groups, is as defined and illustrated above, monosubstituted witha hydroxyl group. (Lower)alkoxy (lower)alkyl contemplates (lower)alkylgroups, as defined and illustrated above, monosubstituted with (lower)alkoxy groups defined and illustrated above. Phenoxy (lower)alkylcontemplates (lower)alkyl groups, as defined and illustrated above,monosubstituted with a phenoxy group. (Lower)alkanoylamino contemplatesalkyl- CONH- of from about two to about 6 carbon atoms, straight. chainand branched, illustrative members of which are acetylamino,n-propionylamino, n-butanoylamino, n-pentanoylamino, hexanoylamino,Z-methylpentanoylarnino and the like. The term halo contemplates fluoro,chloro, bromo and iodo.

The compounds of this invention can be prepared by a number of methods,but a convenient procedure is outlined as follows:

wherein Y, n, m, R, R R R R and R are as hereinabove defined. Thepathway comprises condensing an appropriately substituted[(Z-quinoxalinylmethylene) amino] alkanol (II) with an appropriatelysubstituted benzoyl chloride or phenylsulfonyl chloride (III).Generally, a mixture of II which a stoichiometrical amount or slightexcess, e.g., about a 10% excess, of III in about 10 to about 30 partsby volume of pyridine can be allowed to stand at temperatures of fromabout C. to about 30 C., but preferably at about 10 C., for from about 1hour to about 16 hours, during which time condensation is substantiallycompleted. The product can be recovered in any usual way, but oneconvenient means comprises pouring the mixture into several volumes,e.g., 2-10 volumes, of ice water. This causes product I to precipitateand it can be recovered by filtration. If desired, product I can bepurified by recrystallization, e.g., from chloroform-hexane,benzene,-hexane, cyclohexane-benzene, and the like.

The starting materials of Formula III, the benzoyl chlorides orphenylsulfonyl chlorides are commercially available and can be easilyprepared. Starting materials of Formula II, the [(2quinoxalinylmethylene)amino] alkanols, which those skilled in the artwill recognize to be Shilf bases, can be prepared by condensing a quinoxaline-Z-carboxaldehyde (IV) with an appropriate amine (V) in areaction-inert organic solvent for a period of from about one to aboutthree hours at a temperature range of from about 25 C. to about thereflux temperature of the reaction mixture, according to the followingpathway:

1'13 (32) lgi R4 1 .HM... a. .41.... B

y CHO IV V R 1'13 (I'm) R1 R CH=NCH- CH u-$1I-OII wherein 11, R R R Rand R are as hereinabove defined. Preferably the reaction is conductedin benzene at reflux temperatures for a period of about 1.5 hours withremoval of water by azeotropic distillation. When the reaction iscomplete the resulting quinoxaline-2-carboxaldehyde Schifi base (II) isseparated by conventional recovery procedures, e.g., the solvent isevaporated and the residue recrystallized from a suitable solvent, e.g.,hexane, tetrahydrofuran, cyclohexane, an ethyl acetate-cyclohexanemixture and the like. These procedures are exemplified in detail incopending United States patent application Ser. No. 765,975, John R.Potoski and Meier E. Freed, filed Oct. 8, 1968, entitled Schifi Bases ofQuinoxaline-Z-Carboxaldehydes and Their Reduction Products.

The compounds of Formula I of this invention have demonstratedpharmacological activity. In particular they have been found to exert adepressant action on the central nervous system when tested understandard and accepted pharmacological procedures in laboratory animals,such as mice and rats. They are, therefore, deemed to possess utility inexperimental and comparative pharmacology and are of value to treatconditions in animals, such as valuable domestic animals, and inlaboratory animals, such as mice, rats and the like; responsive totreatment with central nervous system depressant agents, such as theneed to induce a calming elfect.

The compounds of Formula I of this invention may be administered aloneor in combination with other pharmacologically-active ingredients.Whether singly or in combination, they may be used in the form of solidcompositions for oral administration combined, if desired, withextenders or carriers which are relatively non-toxic or inert. They maybe put into tablet, capsule or powder form. On the other hand, they maybe administered in liquid form as a suspension or solution in a suitablevehicle for parenteral use. By way of illustration pharmacologicalaction as central nervous system depressant agents in mice have beendemonstrated when the compound is administered at dosages of 12.7, 40,127 and 400 mg./kg.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples aregiven by way of illustration and are not to be construed as limitationsof the invention, many variations of which are possible withoutdeparting from the spirit or scope thereof.

Example 1.-2-(2-quinoxalinyl) -3-(p-tolylsulfonyl) oxazolidine Asolution of 2.0 g. (0.010 mole) of2-[(2-quinoxalinylmethylene)amino]ethanol and 2.2 g. (0.011 mole) ofp-toluenesulfonyl chloride in 40 ml. of pyridine is allowed to stand at10 C. overnight and then is poured into 150g. of ice water. The whitesolid which precipitates is filtered and dried in vacuo to yield 3.2 g.yield) of product with M.P. 153-15 6 C. Recrystallization fromchloroformhexane gives 3.0 g. of pure product with M.P. 155- 156 C.

Analysis.-Calcd. for C H N O S (percent): C, 60.82; H, 4.82; N, 11.82.Found (percent): C, 61.05; H, 4.72; N, 11.52.

Example 2.3- (p-fluorophenylsulfonyl 2-(2-quinoxalinyl)oxazolidine Asolution of 2-[(2-quinoxalinylmethylene)amino] ethanol (1.5 g.) and 1.5g. (0.075 mole) of p-fiuorobenzenesulfonyl chloride in 25 ml. ofpyridine is allowed to stand at 10 C. overnight then is puored into g.of ice water and filtered to, obtain 2.0 g. (74% yield) of product withM.P. 160 C. Recrystallization of the product twice from hexane-benzenealfords 1.55 g. with M.P. 159161 C.

Analysis.Calcd. for C H N O SF (percent): C, 56.81; H, 3.93; N, 11.69;S, 8.82. Found (percent): C, 57.02; H, 4.23; N, 11.62; S, 8.89.

Example 3.-2-(2-quinoxa1inyl)-3-(3,4,5-trimethoxybenzoyl) oxazolidine Asolution of 1.0 g. (0.005 mole) of2-[(2-quinoxalinylmethylene)amino]ethanol and 1.2 g. (0.005 mole) of3,4,5-trimethoxybenzoyl chloride in 25 ml. of pyridine is allowed tostand at 10 C. overnight and is then poured into 100 g. of ice water. Onstanding a white solid precipitates which on filtration gives crudeproduct with M.P.

138-140 C. Recrystallization ofthe crudeproduct affords 0.85 g. (43%yeld) of a'pure product with M.P.-

Analysis.Ca1cd. for C H N O (percent): C, 63.79; H, 5.35; N, 10.63.Found (percent): C, 63.87; H, 5.18; N, 10.64.

Example 4.-Tetrahydro2- 2-quinoxalinyl)3-(p-tolylsulfonyl)-2H-1,3-oxazine A solution of 2.7 g. (0.012 mole) of3-[(2-quinoxalinylmethylene)amino]propanol and 2.6 g. (0.013 mole) ofp-toluenesulfonyl chloride in 25 ml.- of pyridine is allowed to stand at10 C. for 5 hours and is then poured into 150 g. of ice water.Filtration gives 3.9 g. (88% yield) of product with M.P. 119-12l C.Recrystallization of the product from cyclohexane-benzene affords 3.4 g.(74% yield) of pure product with M.P. 123-125 C.

Analysis.-Calcd. for C gH N O S (percent): C, 61.78; H, 5.19,; N, 11.38;S, 8.68. Found (percent): C, 61.58; H, 4.94; N, 11.62; S, 8.73.

Example 5 .-5 -phenyl-2- (2-quinoxalinyl 3-(p-to1ylsu1fonyl)oxazolidineExample 6.="-4-methyl'-5-phenyl-2- (2-quinoxalinyl)-3- 1p-tolylsulfonyl)oxazolidine A solution of 1.80 g. (0.0062 mole) ofa-(1-[(2-quinr oxalinylmethylene)amino]ethyl)benzyl alcohol and 1.4 g. aof p-toluenesulfonyl chloride in ml. of pyridine is allowed to stand at10 C. for 1 hour and is then poured into 100 g. of ice water. Filtrationgives 2.7 g. (98% yield) of product with M.P. 17 6 184" C.Recrystallization of the product from cyclohexane-benzene gives 1.7 g.(62% yield) of pure product with M.P. 186-188 C. Analysis. Calcd. for CH 'N O S (percent): C, 67140;'H, 5.20; N,' 9.43; S. 7.20. Found(percent): C,

67.73; H, 5.27; N, 9.72; S, 7.41.

Example 7 The procedure of Example 2 is repeated substitutingappropriate Schilf bases fromcopending application Ser. No. 765,975,filed Oct. 8, 1968, and those prepared by procedures disclosed therein,and the following com- 20 pounds of Formula I of this invention areobtained:

The procedure of Example 2 is repeated, substituting correspondingbenzoylchlorides and phenylsulfonyl chlorides for benzene-sulfonylchloride and the following compounds of Formula I of this invention areobtained:

R R R R H H H 5-011 0 H G (3-01 7-C1 0 H H fi-CHa 7-CH3 O H H7-OHa(CH2)2CH2 H 0 H H 6-CH3O 7-CH3O 0 H H 7-CH3CONH H 0 H H H 7-CH3CH2O0 H H 6-CH3O 7-C 3 O H H 8-CH3(CH2)2CH2 H 0 CH3 H H H 0 CHzOH H H H 0CHzOCHs H H H 0 H H H 0 H :12: H H

-- OCH3 0 H 2...... H II -CH2O 0 H :2..'.': H H

- OFa 0 H H H 0 H Q E H 0 H H H 0 H H H n R R2 R3 R H G-OH 7-OH3 0 H ENECH3CH2CH2O g IHI -NOz "-11 0 H H H 1 H 11 'E-QIII N 2-(2-quino'xalinyl)-3 (p tolylsu lfonyl) oxazolidine, administered intraperitoneally(i.p.),.icaus'ed decreased mo- 1r tor activity and decreased respirationat 12.7 mg./kg.; N G 3-(p-fluorophenylsulyfonyl) 2 '-f(2'-quinoxalinyDoXa- NAJHQ zolidine, administered perorally (p.o.),' causeddecreased 1 (R)m motor activity at 127 mg./kg.; and, administered i.p.,442: caused decreased motor activity and decreased respiration at 40mg./kg.;

2-(2-quinoxa1inyl) 3-- 3,4,5 g trimethoxybenZoyDoxam R Y zolidine,administeredpo, caused decreased'inotoractiv- I ity and decreasedrespiration at400 mg./kg.; and i iigfizge 58f Tetrahydro-Z-(Zquinoxalinyl).- 3 (p.- tolylsulfonylk a s ngs-c1130 so; 2r2H-1,3-oxazine, administered p.0 caused decreased motor $53 $8 0activity and decreased'respiratio'n at 40 rng.j/kg. 'l."here 1 2:-F COwere no deaths following administration of'thesecom- @12 E8 pounds atthe highest dose used, 4 00: g/kg; 1 1 41-1 502 We claim: 1 $1 32 28;30 1. A compound of the'formula: 1 4-CF3 S02 1 ouncrnnom so. R -/o- (31m.cu 33,2 35 R The procedure of Example 2 is repeated substitutingappropriate starting materials and the following compounds of thisinvention are obtained:

3 (p fiuorophenylsulfonyl) 2 (2 quinoxalinyl)- oxazolidine, M.P. 1159-161" C.;

2-(2-quinoxalinyl) 3 (3,4,5-trimethoxybenzoyl)oxazolidine, M.P., 140142C.;

Tetrahydro-Z-(Z-quinoxalinyl)-3 (p-tolylsu1fonyl)-2-H- 1,3-oxazine,M.P., 123125 C.;

5-phenyl-2-(2-quinoxalinyl) 3 (p tolylsulfonyl)oxazolidine, M.P.,141-143 C.;

4 methyl 5 phenyl-Z-(Z-quinoxalinyl)-3-(p-tolylsulfonyl)oxazolidine,M.P., 186188 C.;

2 (6 nitro-2-quinoxalinyl)-3-(p-tolylsulfonyl)oxazolidine, M.P.,147-149" C.;

3-(2,S-dichlorophenylsulfonyl) 2 (2-quinoxalinyl)oxazolidine, M.P.,110-112 C.;

3-(p-chlorophenylsulfonyl)-tetrahydro 2 (quinoxalinyl)-2H-1,3-oxazine,M.P., l43-145 C.;

3-(p-fluorophenylsulfonyl)-tetrahydro 2 (Z-quinoxalinyl)-2H-1,3-oxazine,M.P., 9193 C.;

2 (6,7 dichloro 2 quinoxalinyl)-3-(p-tolylsulfonyl) oxazolidine;

3-(p-fluorophenylsulfonyl)-tetrahydro 2 (6,7-dichloro-2quinoxalinyl)-2H-1,3-oxazine; and

3- (p-fluorophenylsulfonyl) tetrahydro 2 (6,7 dime'thoxy-2-quinoxalinyl)-2H-1,3-oxazine.

In evaluating the instant compounds for pharmacological activity, theyare tested in vivo by standard methods with the following results:

The compound is administered to three mice (CF-1 14 to 24 grams) as a 1%suspension in Water to which has been added polyoxyethylene sorbitanmonooleate (emulsifier) at each of the following doses: 400, 127, and12.7

The animals are watched for signs of general stimulation, generaldepression and autonomic activity and the observations are evaluated bymethods described in detail in Turner, Screening Methods inPharmacology, Academic Press, New York, p. 80 (1965), in the sectionentitled A Test Group for Central Depressants.

wherein Y is CO or S0 11 is 0 or '1, m is 1', 2,01' 3; R is (lower)alkyl, (lower) al-koxy, or 'halo; R R ,and'l{ are hydrogen, (lower)alkyl, 'or-phenyl; and R' and R are hydrogen or nitro.'

2. A compound as defined in claim 1'which is2-(2-quinoxalinyl)-3-(p-tolylsulfonyl)oXazolidine. 1 If" 3. A compound asdefined inaclaim 1 which is 3-(pfluorophenylsulfonyl) 2 (2 quinoXalinyl-oxaz0lidine.

4. A compound as defined in-c'l aim' l-which'is 2-(2- quinoxalinyl -3-3,4,5- tri-methoxybenzoyl) oxazolidine.

5. A compound as. defined in claiml which istetrahydro-2-(2quinoxalinyl)- 3 (p tolylsulfonyl) -2H-1,3- oxazine.

6. A compound as defined in claim 1 which-is S-phenyI- 2- 2- quinoxalinyl -3- (p-tolylsulfo'nyl oxazolidine.

7. A compound as defined in claim 1 which is 4 m ethyl-S-phenyl-Z-(Z-quinoxalinyl) 3 -.(.p-toly lsu lfonyl oxazolidine.

8. A compound asdefined; in claiml which is,2-( 6-nitro-2-quinoxalinyl)-3-(p-tolylsulfonyl)o aZolidineL 9-.. A compound asdefinedin claim -1 which "is 3- .(2,5- dichlorophenylsulfonyl ).-2-(Z-quinoXalir ryl) oxaz olidine,

10. A compound as defined in claim 1 which is3-(pchlorophenyl'sulfonyl)-tetrahydro 2 (quinoxalinyl) -2H- 1,3 oxazine.

11. Acompound as defined inclaim .1 which is;3-(pfluorophenylsulfonyl)tetrahydro- 2- (2 quinoxalinyl)- 2H-1,'3 oxazine.

References Cited Chem. Abstracts, v'ol."6f4: 14314e; Bayer, May 1966;

HENRY R. JILES,- Primary-Examiner V S D. WINTERS, Assistant ExaminerU.S.- Cl. X.'R.

